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€When I have the gout, I feel as if I were walking on my eyeballs,€ Sydney Smith (1771- 1845) memorably remarked. And that still appears to be the case for many of today's sufferers of gout.

Recent reports suggest that approximately one in 40 adults endure this often-agonising disease with only 49 per cent of gout patients being managed €“ of which just 38 per cent receive urate-lowering treatment.¹ And it's not just gout that is under-treated. According to the British Pain Society (BPS) and British Geriatrics Society (BGS), between 25 and 50 per cent of older people in the community experience significant pain.

The first recorded use of the juice from opium poppies (Papaver somniferum) dates from 3,400 BC. Today, opioids are widely used in various formulations, ranging from extended-relapse capsules and patches to 'lollipops'. According to the Health and Social Care Information Centre, the NHS issued 1.1m scripts for oxycodone, 3.3m for morphine sulphate and 7.6m for tramadol in 2012 €“ up 8.3, 15.4 and 6.1 per cent on 2011.

Controversial

Despite this long and widespread use of opioids, some indications remain controversial. A systematic review of 15 placebo-controlled studies €“ six of which followed patients for between six and 24 months €“ reported that opioids produce a mean reduction in pain scores of at least 30 per cent.² That's the good news. However 80 per cent of patients experienced at least one adverse event, usually constipation (41 per cent), nausea (32 per cent) and somnolence (29 per cent)². However, a recent editorial in Addiction commented that €clinical studies fail to demonstrate the long-term efficacy and safety of [prescription opioids] for chronic non-cancer pain€.³

Certainly, doctors are often reluctant to prescribe opioids or, if they do, they are prescribed at inadequate dosages because of concerns about, for example, opioid-induced hyperalgesia, adverse effects, tolerance, dependence and diversion⁴. As Addiction notes, widespread prescribing provides more opportunities for diversion, non-medical use and unintentional poisoning. €This results in stigmatisation of patients considered 'risky' and under-treats those in need,€ the editorial comments.³

Against this background, a meta-analysis of 17 studies involving 88,235 patients suggested €that opioid analgesics for chronic pain conditions are not associated with a major risk for developing dependence€.⁴

Nevertheless, the problem is common enough that pharmacists and other healthcare professionals need to remain alert for the warning signs. For example, the incidence of dependence ranged from 0 to 24 per cent (median 0.5 per cent), with a prevalence of 0 to 31 per cent (median 4.5 per cent).⁴ Further studies should identify when opioids work, in whom, for how long, and their long-term tolerability and abuse potential.

Doctors are often reluctant to prescribe opioids

New insights

Despite being used for millennia, we are still uncovering the subtleties of opioid pharmacology. Andrew Somogyi from the University of Adelaide told the British Pharmacological Society's Pharmacology 2013 meeting that opioids may dock to receptors other than mu receptors. These non-opiate binding sites include toll-like receptor 4 (TLR4), one of a family of pattern recognition receptors that recognise and defend against micro-organisms by up-regulating innate immunity.

For instance, TLR4 triggers the release of pro-inflammatory mediators, including interleukin 1 (IL-1), which increases pain sensitivity and may counter opioid-induced analgesia produced by mu receptors.

In one animal study, IL-1 in the spinal cord reduced the analgesic effect of intrathecal morphine eight-fold. On the other hand, spinal IL-1 receptor antagonists increase the intensity and duration of morphine-induced analgesia.

Changes in the balance of the inflammatory cytokines induced by opioids may contribute to tolerance⁵. However disentangling opiate-receptor mediated tolerance from the anti-analgesic effects of TLR4 signalling can be difficult. Further human studies need to confirm these findings.

The studies are of more than academic interest. €Clinically used opioids activate TLR4 signalling with different potencies to the mu receptor,€ Professor Somogyi added. For example, buprenorphine, a semisynthetic partial agonist, shows affinities for mu and kappa receptors that is 1,000-fold higher than morphine. However, the active metabolite morphine-3-glucuronide has the greatest effect on TLR4 signalling. Professor Somogyi suggested that the balance between these two effects might contribute to the variability in clinical responses to opioids.

Improving pain management

Clearly, numerous clinical, pharmacological and attitudinal factors intersect to result in sub-optimal pain management €“ but there is plenty pharmacists can do to help improve pain management. For example, three general practices with a prescribing pharmacist in East Anglia and the same number in Grampian took part in a study⁶ that randomised 196 patients to:

• Medication review with face-to-face prescribing by the pharmacist
• Pharmacist medication review with feedback to GP and no planned patient contact
• Treatment as usual.

Compared to baseline, 47.7 and 38.6 per cent of patients experienced statistically significant improvements in chronic pain grade in the prescribing and review arm respectively. The 31.3 per cent of patients who showed improvements with treatment as usual was not statistically significant. Depression and anxiety scores also improved in the 'pharmacist prescribing' arm. What is now needed is a larger trial, encompassing community pharmacy.

Unreasonable failure to treat pain is viewed worldwide as poor medicine, unethical practice, and €an abrogation of a fundamental human right€.⁷ It seems that current practice still denies many people this human right.

_REFERENCES

_{1. Ann Rheum Dis}

_{2. Pain 2004; 112:372-80}

_{3. Addiction 2014; 109:182-88}

_{4. Addiction 2012; 108:688-698}

_{5. Brain Behav Immun 2008; 22:1178-1189}

_{6. BMJ Open 2013; 3:e002361}

_{7. Anesth Analg 2007;105:205-21}